Controlled Clinical Study on the Use of Dichloromethylene Diphosphonate in Patients with Breast Carcinoma Metastasizing to the Skeleton

Abstract

Thirty-eight normocalcemic patients with bone metastases from breast carcinoma were randomized to receive dichloromethylene diphosphonate (CL2MDP) in addition to their specific antitumor treatment (chemotherapy and/or hormone therapy), at a dose of 300 mg/day/i.v. or placebo for the first 7 dys. TheCL2MDP treatment then continued at a dose of 100 mg/day/i.m. for 3 weeks and finally at 100 mg/i.m. on alternate days for at least another 2 months. In both groups of patients there was a reduction in the intensity of pain (Scott-Huskisson analog), but there was a more frequent reduction in the daily consumption of analgesics in patients treated with CL2MDP (p = 0.02). Unlike the controls, the patients who received CL2MDPpresented a significant reduction in urinary calcium (p = 0.003) and in hydroxyproline (p = 0.05) on the 7^th day. As regards the clinical evolution, negative events such as the appearance of hypercalcemia, pathological fractures, new bone lesions or a substantial increase in the preexisting ones, were observed in 9 of the 12 evaluable patients treated with placebo and in 3 out of 9 treated with CL2MDP. Thickening of the preexisting osteolytic lesions was reported in 2 patients treated with CL2MDP. Tolerance was excellent: only a few patients complained of pain at the intramuscular drug injection site.

Clodronate improves bone mineral density in post-menopausal breast cancer patients treated with adjuvant antioestrogens

“…Compared with tamoxifen, toremifene is more oestrogen antagonistic than agonistic in rat (Di Salle et al, 1990). At present, no data are available on the effect of toremifene on bone.Since bisphosphonates prevent post-menopausal bone loss (Chesnut 1984; Reginster et al, 1989;Storm et al, 1990;Watts et al, 1990;Giannini et al, 1993;Harris et al, 1993;Reid et al, 1994;Filipponi et al, 1995;Liberman et al, 1995) and in advanced breast cancer reduced the development of new bone metastases (Elomaa et al, 1983;Martoni et al, 1991;Paterson et al, 1993;Van Holten Verzantvoort et al, 1993), they are attractive candidates for the treatment of patients with early breast cancer. We performed a prospective, open, randomized study to determine the effect of oral clodronate in post-menopausal women with primary breast cancer treated with adjuvant antioestrogens, Received 24 July 1996 Revised 10 October 1996 Accepted 15 October 1996 Correspondence to: Elomaa, Department of Oncology, Helsinki University Central Hospital, Haartmaninkatu 4, FIN-00290 Helsinki, Finland tamoxifen or toremifene.…”

Bisphosphonate Therapy in Metastatic Breast Cancer

“…Five further controlled trials have been published on the effects of bisphosphonate treatment in breast cancer metastasized to the skeleton ( Table 1) (10)(11)(12)(13)(14). In one of these studies only short-term biochemical results have been published, In two of these other long-term studies clodronate was used (11,12) and pamidronate in the other two (10,15). Details of the design of these trials are presented in Table 1 and results on biochemical parameters and clinical endpoints in Table 2.…”

Use of Bisphosphonates in Skeletal Metastasis

“…The effectiveness of bisphosphonates has been evaluated by their ability to reduce skeletal events: (1) new bone lesions (x-rays or scintigraphy) ; (2) fractures (radiologic or clinical examination) (11)(12)(13)(14)(15)(16)(17)(18)(19)(20); (3) bone pain (analgesics, visual analogue scale, pain score, requirement of irradiation or isotope therapy) (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41); (4) performance status (Karnofsky, Zubrod, ECOG) (11 -20, 31-41); (5) quality of life measures (16-20, 36, 37, 40, 41); (6) hypercalcemia (11 -21, 25, 31 -38); (7) measurements of different bone markers (11 -13, 20, 28, 30, 35 -38, 40 -44); and (8) survival (11 -13, 15, 18 -20, 34 -38, 40, 41). Study endpoints have been defined as a reduction of skeletal events and complications as well as an improvement of quality of life and pain relief.…”

“…Seven of them were performed in patients with known osteolytic metastases (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Two of the first clodronate studies are not reviewed here because of their small size (11)(12)(13)(14).…”